Minimal Residual Disease Monitoring by T-cell Receptor Repertoire Profiling T-cell neoplasms are generally more aggressive and have poorer outcomes than comparable B-cell lymphomas. In addition, for many of these patients, prognosis following disease relapse is dismal. Detecting the presence or absence of Minimal Residual Disease (MRD) following treatment is emerging as an alternative method to stratify relapse risk and individualize patient treatment. Depending on the type of T cell malignancy, a number of methods are clinically used to detect MRD. However, these assays can only reliably detect MRD in the range of 1:100 to 1:10,000 cells, thus detection is only possible once malignant cells have reached an appreciable frequency, past the point where treatment could be most effective. Herein, we propose a new method for identifying neoplastic lymphoid populations and measuring MRD by direct sequencing of the T-cell receptor (TCR) repertoire using our established high-throughput T-cell receptor sequencing technology. Our semi-quantitative technology is sensitive and can detect clones down to fewer than 1:100,000 cells (10-fold increased sensitivity over standard methods). This method will be further developed and validated for potential clinical applications through a collaborative project using samples from a cohort of mature T-cell lymphoma patients. The findings from this study will not only be relevant for assessment of MRD in T-cell neoplasms; its extension to the detection of MRD in B-cell neoplasms will expand the applicability of this assay to all hematological neoplasms.